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[101]
mimics . Various efforts have been made to develop miRNA-based therapies in the past several years, and
two studies have shown particular promise. The first study focused on the therapeutic silencing of disease-
associated miRNAs using miRNA inhibitors. Miravirsen (Santaris Pharma) is one of several promising
miRNA inhibitors; it can bind to miR-122 and inhibit its biogenesis. Miravirsen was developed for the
treatment of hepatitis C and is currently under evaluation in clinical trials [65-67] . The second study examined
therapeutic miRNA-based drugs through the use of synthetic miRNA mimics. Recently, a phase I clinical
[68]
trial using the miRNA mimic MIRX34 (Mirna Therapeutics, Inc.) was performed . MIRX34 is a synthetic
miRNA mimic of the tumor suppressor miR-34 and was administered to patients with primary or metastatic
liver cancer. This trial was ended because of serious adverse immune-related effects. The administration
of tumor-suppressor miRNA mimics continues to bear undesirable risks and negative, unexpected
physiological effects because multiple genes, regulating multiple biological functions, can be impacted by
miRNAs. Restoring tumor-suppressor miRNAs, which are abundantly detected in the plasma/serum of
healthy individuals but lowered in patients with cancer [Table 2], may minimize the physiological risks of
systemic administration. We recently reported that restoring and maintaining the miR-107 plasma level
[61]
significantly inhibited tumor progression in mice . The systemic delivery of tumor-suppressor miRNAs in
gastric cancer patients may thus provide significant advantages because effects can be repeatedly examined
repeatedly using blood-based miRNA levels.

CONCLUSION
The development of liquid biopsy-based analyses could improve diagnosis and therapy for patients with
gastric cancer. As a liquid biopsy, circulating miRNAs have the potential to diagnose gastric cancer at an
early stage, predict prognosis and recurrence, evaluate patient status and therapeutic efficacy, and provide
optimal, individualized treatment strategies. It should be noted that the present review is limited by
examining a relatively small number of retrospective cohort studies. Additional research with large cohorts
or prospective clinical trials with longer follow-up periods are therefore necessary to confirm the usefulness
of candidate miRNAs. Translation into clinically useful gastric cancer treatments also requires significant
additional work. The physiological effects of tumor-suppressor miRNAs must be examined in greater detail
before they can be safely administered systemically, and their tumor-suppressive functions must be validated
in vivo before clinical use. Delivery systems for miRNAs must be further refined to surmount problems such
as cellular uptake and bloodstream stability. Finally, more powerful anticancer tumor-suppressor miRNAs
should be found by examining the plasma of patients with different cancers, through methods such as
microarray analysis, next-generation sequencing, and digital PCR-based approaches. Currently under
evaluation, these strategies will likely provide the future’s next innovations.

DECLARATIONS
Authors’ contributions
Designed the research and wrote the paper: Komatsu S
Collected the data and performed data analyses: Komatsu S, Kiuchi J, Imamura T
Reviewed the paper: Komatsu S, Ichikawa D, Otsuji E

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflict of interest
All authors declared that there are no conflicts of interest.